4-(2-Benzoylphenyl-1-pyazole and 4-(2-benzoylphenyl)-1-pyrazoline derivatives

ABSTRACT

There are presented compounds of the formula ##STR1## wherein R 1  is hydrogen or lower alkyl; R 6  is halo and R 5  is hydrogen or halo; and compounds of the formulas ##STR2## wherein R 2  and R 3  are selected from the group consisting of hydrogen, lower alkyl, C 2  to C 7  carboxylic acids, hydroxy C 2  to C 7  alkyl, C 2  to C 7  carboxylic acid esters and amides and the group COR 11  wherein R 11  and is selected from the group consisting of alkoxy, amino or mono-lower alkyl amino; R 35  is hydrogen or lower alkyl; R 5  is hydrogen or halo; and R 7  is methyl or chloromethyl, all of which are useful in the preparation of pyrazolobenzazepines.

This is a division of application Ser. No. 286,122 filed July 23, 1981,now U.S. Pat. No. 4,379,765, which is a CIP of U.S. Ser. No. 175,552,filed Aug. 5, 1980 (now abandoned).

DESCRIPTION OF INVENTION

The present invention relates to pyrazolobenzazepines of the formulas##STR3## wherein R₁ is hydrogen or lower alkyl; R₂ and R₃ are selectedfrom the group consisting of hydrogen, lower alkyl, C₂ to C₇ carboxylicacids, hydroxy C₂ to C₇ alkyl, C₂ to C₇ carboxylic acid esters andamides and the group COR₁₁ wherein R₁₁ is alkoxy, amino or mono- loweralkyl amino; R₆ is nitro or halo and R₅ is hydrogen or halo

and the pharmaceutically acceptable salts thereof.

As used herein, the term "halo" or "halogen" or "halide" refers tochloro, bromo and fluoro unless otherwise indicated.

As used herein, the term "lower alkyl" refers to C₁ to C₇carbon-hydrogen radicals which may be straight or branched chain, e.g.methyl, ethyl, propyl, isopropyl, butyl, etc.

By the term "C₂ to C₇ carboxylic acid esters and amides thereof" ismeant substituents of the formulas lower alkyl --COR₁₅ wherein R₁₅ ishydroxy, alkoxy, amino or substituted amino. By substituted amino ismeant an --NH₂ group which may be mono- or di-substituted by loweralkyl, e.g., methylamino or dimethylamino groups.

The N-oxides of compounds of formulas I and II may be formed by reactionof the base compounds with a peracid or by reaction in the case of aformula XVIII compound with hydroxylamine following reaction parameterswell-known in the art.

The following reaction schemes set forth methods for the preparation ofthe compounds of formulas I and II. ##STR4## wherein R₅ is as above andR₆ is halo.

III→IV

The compound of formula III, a well-known starting material, is reactedwith zinc dust and cupric sulfate in concentrated ammonium hydroxide.Reaction temperatures range from about room temperature to 100° C. withabout 100° C. preferred.

IV→V

The compound of formula IV is reacted with a metal hydride, such as,lithium aluminum hydride or borane in an etherial solvent such asdiethyl ether or tetrahydrofuran. Reaction temperatures range from about-78° C. to room temperature with about 0° C. preferred.

V→VI

The compound of formula V is reacted with pyridinium chlorochromate,manganese dioxide or other suitable oxidizing agents using methylenechloride as solvent. Reaction temperatures range from about 0° C. to thereflux temperature of the solvent with about room temperature aspreferred.

VI→VII

The compound of formula VI is reacted with diethylcyanomethylphosphonate in the presence of a strong base such as sodiumhydride, sodium amide etc. and using an ethereal solvent, such as,tetrahydrofuran. Reaction temperatures range from about 0° C. to roomtemperature with about room temperature as preferred.

VII→VIII

The compound of formula VII is reacted with chromium trioxide or anoxidizing agent derived from chromium trioxide in a mixture of aceticacid and methylene chloride. Reaction temperatures range from about 0°C. to about 60° C. with room temperature preferred.

IX→X

The compound of formula IX i.e., the amino ketone is a well-knownstarting material. The compound is reacted with acrylonitrile in thepresence of acetonitrile, a lower alkyl nitrite and cupric chloride. Thereaction temperature may range from about 0° C. to about 40° C. withabout room temperature as preferred.

X→VIII

The compound of formula X above is reacted with an alkali metal, e.g.,lithium, sodium or potassium carbonate and bicarbonate mixturepreferably a mixture of one part potassium carbonate to three partspotassium bicarbonate. Suitable solvents include DMSO, DMF or C₁ to C₄alcohols, e.g., methanol. Reaction temperature ranges from about 20° C.to about 50° C. with room temperature preferred. The above reactionrepresents a dehydrohalogenation which is well-known in the art.

IX→XI

The compound of formula IX may be diazotized using sodium nitrite insulfuric acid and the diazonium salt may be isolated by precipitatingthe respective tetrafluoroborate salts. These salts are slurried inwater and treated with aqueous potassium iodide at room temperature togive the iodobenzophenone XI.

XI→VIII

The compound of formula XI is reacted with acrylonitrile in the presenceof palladium II salt, such as, acetate using acetonitrile or an aromatichydrocarbon, such as, toluene as solvent. Reaction temperatures rangefrom about 60° C. to the reflux temperature of the solvent with refluxtemperature preferred. ##STR5## wherein R₁ and R₅ are as above and R₆ ishalogen and R₇ is selected from the group consisting of lower alkyl or aC₂ to C₇ carboxylic acid ester.

VIII→XII and/or XIII

The compound of formula VIII is reacted with a diazoalkane of theformula

    R.sub.1 --CHN.sub.2

wherein R₁ is as above.

Suitable solvents include ethereal solvents, such as, tetrahydrofuran ordioxane while utilizing methylene chloride as a co-solvent. The reactionis run at between about 0° C. to room temperature with about roomtemperature as preferred.

XII and/or XIII→XIV

The compounds of formulas XII and/or XIII are thereafter reacted with adehydrogenating agent, such as, manganese dioxide in a compatiblesolvent, such as, toluene, tetrahydrofuran or methylene chloride. Thereaction temperature may be varied from room temperature to the refluxtemperature of the selected solvent with the reflux temperaturepreferred.

Alternatively compounds of formulas XII and/or XIII are reacted withbromine in a halogenated hydrocarbon solvent, such as, methylenechloride or chloroform at near room temperature. The dehydrogenation iseffected by heating or by treatment with a mild base. The reactionmixture is then either heated to the reflux temperature of the solventor treated with a mild base, such as, an alkali metal bicarbonate ortrialkylamine.

XIV→Ia

The compound of formula XIV is reacted with hydrogen at pressuresranging from about atmospheric pressure to five atmospheres in thepresence of a transition metal catalyst, such as, Raney nickel usingglacial acetic acid as solvent. Reaction temperature is about roomtemperature. The open amine is first formed in the reduction of XIV andthen cyclizes to Ia.

Ia→Ib and IIb

The compound of formula Ia is reacted with an alkali metal alkoxide,such as, sodium or potassium methoxide or ethoxide, or a lithiumdi-lower alkyl amide followed by a secondary reaction with an alkylatingagent, such as, a lower alkyl halide or sulfonate in an etherealsolvent, such as, tetrahydrofuran, dioxane, dimethylformanide ordimethylsulfoxide. The secondary reaction may also be effected byreaction with a haloester, such as, an ethylbromoacetate orethyl-3-bromopropionate to produce a compound wherein R₇ is a C₂ to C₇carboxylic acid ester. The reaction may be run at between about 0° C. toroom temperature with about 0° C. as preferred. ##STR6## wherein R₁ andR₅ are as above and R₆ is halogen, R₇ ' is a C₂ to C₇ carboxylic acidester, R₈ is a carboxylic acid amide and R₉ is hydroxy C₂ to C₇ alkyl.

Ic→Id and IIc→IId

The compounds of formulas Ic and IIc are reacted with ammonia or a mono-or di-substituted lower alkyl amine and a catalytic amount of thecomplementary hydrochloride salt in a C₁ to C₄ alcoholic solvent. Thereaction is run at about 100° C. utilizing a pressure apparatus tocontain the volatile reactants.

Ic→Ie and IIc→IIe

The compounds of formulas Ic and IIc are reacted with a metal hydridereducing agent, such as, lithium aluminum hydride in an etherealsolvent, such as, tetrohydrofuran or dioxane.

The reaction is run at about -78° C. to room temperature with about 0°C. as preferred. ##STR7## wherein R₁ and R₅ are as above and R₆ ishalogen, R₁₂ is amino or mono- lower alkylamino and R₁₃ is lower alkoxy

Ia→If and IIf

The compound of formula Ia is reacted with a lower alkyl or alkali metalisocyanate in an ethereal solvent, such as, tetrahydrofuran or dixane ofa chlorinated hydrocarbon, such as, methylene chloride or chloroform.The reaction is effected at from about -20° C. to room temperature withabout 0° C. as preferred.

Ia→Ig and IIg

The compound of formula Ia is reacted with an alkali metal alkoxide,such as, a sodium or potassium ethoxide or butoxide or with a lithiumdi-lower alkylamide followed by a halo formate, such as, methylchloroformate, benzyl chloroformate, etc. in an ethereal solvent, suchas, tetrahydrofuran or dioxane or in dimethylformamide. The reaction isrun at between about -78° C. to room temperature with about 0° C. aspreferred. ##STR8## wherein R₂, R₃ and R₅ are as above, R₃₅ is hydrogenor lower alkyl.

The dotted lines found at the R₂ and R₃ substitution points and in thepyrazolo-ring indicate the alternate nature of substitution andunsaturation, i.e., where there is a R₂ then there is no R₃ and theunsaturation occurs at 1,2 and 4,5 whereas when there is a R₃substituent, then unsaturation is 2,3 and 1,5.

Following the reactions of steps Ia→Ib, Ia→IIb, Ic→Id, IIc→IId thecompound of formula XIX wherein R₂ and R₃ are hydrogen may be modifiedto provide R₂ and R₃ equal to lower alkyl, C₂ to C₇ carboxylic acidesters and amides and the group COR₁₁ wherein R₁₁ is alkoxy, amino ormono-lower alkylamino.

XV→XVI

The compound of formula XV may be produced by following methods known inthe art.

The compound of formula XV is reacted with a dicarbonyl compound of theformula ##STR9## wherein R₃₅ is as above in the presence of a strongbase, such as sodium hydride or a potassium or sodium methoxide.Suitable solvents are polar aprotic solvents, such as,dimethylsulfoxide, dimethylformamide or tetrahydrofuran. The reactionmay be run from between about -10° C. to 100° C. with about roomtemperature preferred.

XVI→XVII

The compound of formula XVI is thereafter reacted with a hydrazine saltor a substituted hydrazine salt, a hydrazine substituted with theparticular R₂ or R₃ substituent which is desired. The salts may bemineral acid salts, such as, the hydrochlorides or sulfates. Suitablesolvents include C₁ to C₄ aqueous alcoholic solutions. The reaction maybe run at from about room temperature to reflux temperature with refluxtemperature of the selected solvent as preferred.

XVII→XVIII

The compound of formula XVII is thereafter reacted with a halogenatingagent, such as, t-butyl hypochlorite or N-bromosuccinimide. Suitablesolvents include non-polar solvents, such as, methylene chloride,benzene or toluene. The reaction may be run at between about 0° C. toreflux temperature of the solvent with about room temperature aspreferred.

XVIII→XIX

The compound of formula XVIII is reacted with ammonia or hydroxylaminein the presence of a solvent, such as, tetrahydrofuran,dimethylformamide, dimethylsulfoxide and methylene chloride. Thereaction is carried out at between about -40° C. to reflux with apreferred range of from about room temperature to 50° C. The openhydroxylamine spontaneously cyclizes to the desired end product.

Preferred compounds of formulas I and II are those wherein R₁ is asabove, R₂ and R₃ are hydrogen and lower alkyl and R₅ and R₆ are asabove.

Especially preferred compounds of formulas I and II are those of theformulas:

8-chloro-6-(2-fluorophenyl)-2H,4H-pyrazolo[3,4-d][2]benzazepine

8-chloro-6-phenyl-2-(2-hydroxyethyl)-2H,4H-pyrazolo[3,4-d][2]benzazepine

6-(2-chlorophenyl)-3-methyl-8-nitro-2H,4H-pyrazolo[3,4-d][2]benzazepine

8-chloro-2-/(methylamino)carbonyl/-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine

The expression "pharmaceutically acceptable salts" is used to includesalts with both inorganic and organic pharmaceutically acceptable strongacids, such as, sulfuric acid, hydrochloric acid, nitric acid,methanesulfonic acid and p-toluenesulfonic acid. Such salts can beformed quite readily by those skilled in the art with the prior art andthe nature of the compound to be placed in salt form in view.

The pharmaceutical activities of the instantly claimed compounds areindicated by the pharmacological data set forth below for the compoundsof the invention.

    __________________________________________________________________________    Tests                                                                         Compounds        Footshock                                                                           Inclined Screen                                                                       Unanesthetized Cat                             __________________________________________________________________________    8-chloro-2-(methyl-                                                                            25 mg/kg                                                                            400 mg/kg                                                                             20 mg/kg                                       amino)carbonyl-6-                                                             phenyl-4H--pyrazolo-                                                          3,4-d-2-benzazepine                                                           8-(2-chlorophenyl)-3-  400 mg/kg                                                                             250 mg/kg                                      methyl-6-nitro-2H,10H--                                                       pyrazolo-3,4-d-2-benzazepine                                                  Toxicity (LD.sub.50) = greater than                                           1000 mg/kg (PO)                                                               8-chloro-6-(2-chloro-                                                                          25 mg/kg                                                                            143 mg/kg                                                                             10 mg/kg                                       phenyl)-2H,4H--pyrazolo-                                                      3,4-d-2-benzazepine half                                                      molar dichloromethane solvate                                                 Toxicity (LD.sub.50) = 800 mg/kg (PO)                                         8-chloro-2-(2-hydroxy-                                                                         100 mg/kg                                                                           40 mg/kg                                                                              20 mg/kg                                       ethyl)-6-phenyl-2H,4H--                                                       pyrazolo-3,4-d-2-benzazepine                                                  Toxicity (LD.sub.50) = 750 mg/kg (PO)                                         8-chloro-6-(2-fluoro-                                                                          25 mg/kg                                                                            66 mg/kg                                                                              2 mg/kg                                        2H,4H-pyrazolo-3,4-d-2-                                                       benzazepine                                                                   Toxicity (LD.sub.50) = 760 mg/kg (PO)                                         __________________________________________________________________________

A summary of the pharmacological tests which are known in the art is asfollows.

Footshock

A pair of mice is confined under a one liter beaker placed on a gridwhich presents shock to the feet. At least 5 fighting episodes areelicited in a two-minute period. Pairs of mice are marked and pretreated1 hour to a second shocking. Logarithmic dose intervals are utilized upto a maximum of 100 mg/kg. At the 100% blocking dose, 3 out of 3 pairsmust be blocked from fighting.

Inclined Screen

Groups of 6 male mice are given the test drug (maximum dose of 500mg/kg) and then are left on the inclined screen at least 4 hours forobservation of paralyzing effects severe enough to cause them to slideoff the screen. If activity is observed, additional doses are takenuntil at least two are reached at which some, but not all of the animalsslide off the screen. Doses at which mice fall off the screen due totoxicity or excitation are not included in the calculation of PD₅₀.

Unanesthetized Cat

Cats are treated orally and observed for minimum symptoms--usuallyataxia. One cat is used at a dose of 50 mg/kg. If activity is present,up to three cats/dose are used. Results are given as minimum effectivedose.

The pyrazolo[3,4-d][2]benzazepines above are useful as pharmaceuticalsand are characterized by activity as sedatives and anxiolytic agents.These compounds can be used in the form of conventional pharmaceuticalpreparations; for example, the aforesaid compounds can be mixed withconventional organic or inorganic, inert pharmaceutical carrierssuitable for parenteral or enteral administration such as for example,water gelatin, lactose, starch, magnesium stearate, talc, vegetable oil,gums, polyalkylene glycols, Vaseline or the like. They can beadministered in conventional pharmaceutical forms, e.g., solid forms,for example, tablets, dragees, capsules, suppositories or the like, orin liquid forms, for example, solutions, suspensions or emulsions.Moreover, the pharmaceutical compositions containing compounds of thisinvention can be subjected to conventional pharmaceutical expedientssuch as sterilization, and can contain conventional pharmaceuticalexcipients such as preservatives, stabilizing agents, wetting agents,emulsifying agents, salts for the adjustment of osmotic pressure, orbuffers. The compositions can also contain other therapeutically activematerials.

A suitable pharmaceutical dosage unit can contain from about 1 to about500 mg of the benzazepine end products with a dosage range of from about1 mg to about 100 mg being the preferred oral administration and adosage range of from about 1 mg to about 50 mg being preferred forparenteral administration. However, for any particular subject, thespecific dosage regiment should be adjusted according to individual needand the professional judgement of the person administering orsupervising the administration of the aforesaid compounds. It is to beunderstood that the dosages set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of thisinvention.

The term "dosage unit" as employed throughout this specification refersto pharmaceutically discrete units suitable as unitary dosages formammalian subject each containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle.

The following examples are illustrative, but not limitative of thisinvention. All temperatures given are in degrees centigrade, unlessindicated otherwise.

EXAMPLE 1 2-Benzyl-4-chlorobenzoic Acid

To a solution of 5.0 g of cupric sulfate in 3 liters of concentratedammonium hydroxide was added 300 g (4.6 mole) of activated zinc dust and100 g (0.42 mole) of 2-benzoyl-4-chlorobenzoic acid. The mixture wasrefluxed for 3 days, during which the volume was maintained by theaddition of concentrated ammonium hydroxide. The mixture was cooled, andthe excess zinc was removed by filtration. The filtrate was acidified bythe addition of concentrated hydrochloric acid to a pH of 3. Theresulting precipitate was collected by filtration, and dried to constantweight to give a white solid with mp 142°-144°.

EXAMPLE 2 2-Benzyl-4-chlorobenzyl alcohol

To a solution of 28.4 g (0.75 mole) of lithium aluminum hydride in 800ml of ether, which was cooled to 0°, was added dropwise 85.1 g (0.345mmole) of 2-benzyl-4-chlorobenzoic acid in 250 ml of ether. The mixturewas allowed to warm to room temperature, and was stirred for 2 hr. Theexcess lithium aluminum hydride was discharged by the addition of 28.5ml of water, 28.5 ml of 10% aqueous sodium hydroxide, and 85.5 ml ofwater. The precipitate was removed by filtration and the filtrate wasdried with sodium sulfate. Removal of the ether at reduced pressure gavea colorless oil which crystallized upon standing, mp 46.5°-49°.

EXAMPLE 3 2-Benzyl-4-chlorobenzaldehyde

To a suspension of 238 g (1.1 mole) of pyridinium chlorochromate and 800ml of methylene chloride was added 79.3 g (0.34-mole) of2-benzyl-4-chlorobenzyl alcohol. The mixture was stirred at roomtemperature for 2 hr. The chromium salts were precipitated by theaddition of 2.4 liters of 1:1 ether:petroleum ether, and the precipitatewas removed by filtration through Celite. The solvent was removed atreduced pressure to give a yellow oil, which was used without furtherpurification.

EXAMPLE 4 3-[2-Benzyl-4-chlorophenyl]-2-propenonitrile

To a suspension of 10.5 g (0.437 mole) of mineral oil free sodiumhydride in 1.2 liters of tetrahydrofuran was added dropwise 58.4 g(0.328 mole) of diethylcyanomethyl phosphonate. After the hyrogenevolution had ceased ca 60 min, 69.4 g (0.3 mole) of2-benzyl-4-chlorobenzaldehyde, in 75 ml of tetrahydrofuran was addeddropwise. The mixture was stirred overnight at room temperature. Thetetrahydrofuran solution was decanted, and concentrated at roomtemperature. The residue was partitioned between 2 liters of water and1.5 liters of ether. The ether solution was separated, washed withwater, and dried with sodium sulfate. The ether was removed at reducedpressure to give a yellow oil which was used without furtherpurification.

EXAMPLE 5 4-[2-Benzoyl-4-chlorophenyl]pyrazole-3-carbonitrile

A mixture of 0.4 mole of diazomethane in 400 ml of ether and 18.2 g(0.068 mole) of 3-(2-benzoyl-4-chlorophenyl)-2-propenonitrile wasallowed to stand at room temperature overnight. The excess diazomethanewas discharged by the dropwise addition of 30 ml of acetic acid. Theether solution was washed with 5% aqueous sodium carbonate and water.The ether solution was dried (Na₂ SO₄), and was concentrated at reducedpressure to give a yellow oil.

A mixture of 21.0 g of the yellow oil, 11.1 g (0.069 mole) of bromine,17 g (0.204 mole) of sodium bicarbonate and 300 ml of chloroform wasstirred at room temperature overnight. The excess bromine was dischargedby the addition of 200 ml of saturated aqueous sodium bisulfite. Thechloroform solution was separated, washed with water, and dried withsodium sulfate. Concentration of the chloroform solution at reducedpressure gave a yellow oil. Purification by column chromatography (800g, SiO₂ ; 4:1 methylene chloride:ether) gave a white solid, mp194°-195°.

EXAMPLE 6 8-Chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]-benzazepine

A mixture of 2.2 g (7.2 mmole) of4-[2-benzoyl-4-chlorophenyl]pyrazole-3-carbonitrile, 2.0 g of Raneynickel, and 150 ml of acetic acid was hydrogenated on a Parr apparatusfor 4 hr. The Raney nickel was removed by filtration, and the filtratediluted with 600 ml of ice water. The acetic acid was neutralized withconcentrated ammonium hydroxide and the resulting aqueous solution wasextracted with methylene chloride. The methylene chloride solution waswashed with water, and was dried with sodium sulfate. Concentration ofthe methylene chloride solution gave a tan solid. Recrystallization fromchloroform/hexane gave a white solid, mp 241°-243°.

EXAMPLE 7 4-(2-benzoyl-4-chlorophenyl)-3-cyano-5-methylpyrazole

A solution of diazoethane in 400 ml of ether (prepared from 16.1 g (0.1mol) of N-ethyl-N'-nitro-N-nitrosoimino urea,) was added to a solutionof 15 g (0.056 mol) of crude3-(2-benzoyl-4-chlorophenyl)-2-propenonitrile in 100 ml of ether. Afterstanding at room temperature for 3 hr, the excess diazoethane wasdestroyed by addition of glacial acetic acid. The mixture was washedwith saturated sodium bicarbonate solution, was dried and evaporated, atthe end azeotropically with toluene. The residue was dissolved in 400 mlof toluene and the solution was heated to reflux for 11/2 hr in presenceof 60 g of activated manganese dioxide. The water was separated in aDean Stark trap. The MnO₂ was removed by filtration over Celite and thefiltrate was evaporated. The residue (14 g) was chromatographed over 300g of silica gel using 10% (v/v) of ethyl acetate in methylene chloride.The homogenous fractions were combined and evaporated to yield an oilyproduct.

EXAMPLE 8 8-Chloro-1-methyl-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine

A mixture of 1.8 g of resinous4-(2-benzoyl-4-chlorophenyl)-3-cyano-5-methylpyrazole, 35 ml of glacialacetic acid and ca. 10 g of Raney nickel was hydrogenated at atmosphericpressure for 6 hr. The catalyst was filtered off and the filtrate wasevaporated. The residue was partitioned between methylene chloride/etherand 10% aqueous sodium carbonate solution. The organic phase was driedand evaporated and the residue was crystallized from ether to yieldcrude product which was recrystallized from ether to give off-whitecrystals with mp 145°-150° (foaming).

The mother liquor was chromatographed over 30 g of silica gel usingethyl acetate/methylene chloride 3:1. Crystallization of the combinedclean fractions from ether/hexane gave additional product.

This was combined with the first crop and dissolved in hot ethanol.Ethanolic hydrogen chloride was added and the hydrochloride wascrystallized by addition of ether. The yellow needles were collected anddried to yield end product with mp 290°-295°. The analytical sample wasrecrystallized from methanol/ether.

EXAMPLE 98-Chloro-N-methyl-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-carboxamideand8-Chloro-N-methyl-6-phenyl-3H,4H-pyrazolo[3,4-d][2]benzazepine-3-carboxamide

Methyl isocyanate, 2 ml, was added to a solution of 0.9 g (3.07 mmol) of8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine in 50 ml ofmethylene chloride and the mixture was allowed to stand at roomtemperature for 2 hr. The solvent was evaporated and the residue wascrystallized from ethyl acetate to yield the 2-carboxamide as whiteneedles with mp 230°-235°.

The mother liquor was evaporated and the residue was chromatographedover 65 g of silica gel using 20% (v/v) of ether in benzene.Crystallization of the combined clean fractions from ethylacetate/hexane gave the 3-carboxamide with mp 188°-190° and 248°-250°dec.

EXAMPLE 108-Chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetic acidethyl ester and8-Chloro-6-phenyl-3H,4H-pyrazolo[3,4-d][2]benzazepine-3-acetic acidethyl ester

To a solution of 1.2 g (4.1 mmole) of8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine in 35 ml of drytetrahydrofuran, which was cooled to -20°, was added 9.0 ml (4.5 mmole)of a 0.5M tetrahydrofuran solution of lithium disopropylamine. Themixture was allowed to warm to room temperature followed by the additionof 0.5 ml (4.5 mmole) of ethyl bromoacetate. The mixture was stirred for5 hr at room temperature, was poured into 100 ml of water, and wasextracted with ether. The ether solution was dried with sodium sulfate,and concentrated at reduced pressure to give a yellow foam. Purificationby column chromatography (30 g SiO₂, 9:1 methylene chloride/ether) gavetwo major components: the 3-acetic acid ethyl ester as a yellow foam.The later fractions gave the 2-acetic acid ethyl ester as a yellow foam.

EXAMPLE 118-Chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetamide

Heating a mixture of 0.8 g (2.1 mmol) of8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetic acidethyl ester and 20 ml of methanolic ammonia (ca. 20%, v/v) in anautoclave on the steam bath for 20 hr gave after crystallization fromethyl acetate/ether colorless crystals with mp 236°-238°. The analyticalsample was recrystallized from ethyl acetate/methylene chloride/ether.

EXAMPLE 128-Chloro-6-phenyl-3H,4H-pyrazolo[3,4-d][2]benzazepine-3-acetamide

A mixture of 0.4 g (1.05 mmol) of8-chloro-6-phenyl-3H,4H-pyrazolo[3,4-d][2]benzazepine-3-acetic acidethyl ester and 20 ml of methanolic ammonia (ca 20% v/v) was heated inan autoclave on the steam bath overnight. The solvent was evaporated andthe residue was purified by chromatography over 15 g of silica gel using5% (v/v) of ethanol in methylene chloride. Crystallization from ethylacetate/ether gave colorless crystals with mp 218°-219°.

EXAMPLE 138-Chloro-2-(2-hydroxyethyl)-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine

A solution of 0.4 g (0.01 mol) of lithium aluminum hydride in 80 ml ofether was cooled to -30°. A solution of 0.8 g (2.1 mmol) of8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetic acidethyl ester in 5 ml of tetrahydrofuran was added and the mixture wasstirred at -10° to -5° for 15 min. The reaction mixture was hydrolizedby addition of 2 ml of water, diluted with methylene chloride andfiltrated over Celite. The filtrate was evaporated and the residue wascrystallized from ether to yield colorless crystals which wererecrystallized for analysis from ethyl acetate, hexane, mp 173°-175°.

EXAMPLE 14 3-(2-Benzoyl-4-chlorophenyl)-2-propenenitrile

A mixture of 28.8 g (0.14 mole) of3-[2-benzyl-4-chlorophenyl]-2-propenentrile, 50 g (0.5 mole) of chromiumtrioxide, 100 ml of methylene chloride, and 300 ml of acetic acid wasstirred at room temperature overnight. The excess chromium trioxide wasdischarged by the slow addition of 30 ml of ethanol. The mixture wasdiluted with 800 ml of water, and extracted with 500 ml of ether. Theether solution was washed with water, saturated aqueous sodiumbicarbonate, and saturated aqueous sodium chloride. The ether solutionwas dried with anhydros sodium sulfate, and concentrated at reducedpressure to give a yellow oil which was used without furtherpurification.

A sample of the product was purified by preparative layer chromatography(SiO₂ ; 2 mm; 1:1 methylene chloride:pentane) to give a white solid, mp87°-89°.

EXAMPLE 15 α,4-dichloro-2-(benzoyl)-benzenepropanenitrile

A solution of 92.7 g (0.4 mole) of 2-amino-5-chlorobenzophenone in 250ml of acetonitrile was added to a mixture of 70 g (0.52 mole) of cupricchloride, 65 g (0.63 mole) of t-butylnitrite, 500 ml of acrylonitrile,and 500 ml of acetonitrile. When the addition was complete stirring atroom temperature was continued for 2 hr. The mixture was diluted with 80ml of 6N hydrochloric acid and 1500 ml of water, extracted with etherand dried over anhydrous sodium sulfate. The ether solution wasconcentrated at reduced pressure to give a brown oil, which containedthe end product and 2,5-dichlorobenzophenone. Trituration of the oilwith a mixture of ether and petroleum ether gave the end product as atan solid. Recrystallization of a small portion of the end product froma mixture of ether and petroleum ether gave pale yellow needles, mp69°-71°.

EXAMPLE 16 α,4-dichloro-2-(2-fluorobenzoyl)-benzenepropanenitrile

The preparation ofα-4-dichloro-2-(2-fluorobenzoyl)-benzenepropanenitrile was conducted inthe same manner as the preparation ofα-4-dichloro-2-(benzoyl)-benzenepropanenitrile to give pale yellowprisms, mp 94°-95°.

EXAMPLE 17 α,4-dichloro-2-(2-chlorobenzoyl)-benzenepropanenitrile

The preparation ofα,4-dichloro-2-(2-chlorobenzoyl)-benzenepropanenitrile was conducted inthe same manner as the preparation ofα,4-dichloro-2-(benzoyl)-benzenepropanenitrile to give off-white prisms,mp 102°-103°.

EXAMPLE 18 3-(2-benzoyl-4-chlorophenyl)-2-propanenitrile

A mixture of 50.9 g (0.168 mole) ofα,4-dichloro-2-(benzoyl)-benzenepropanenitrile, 17 g (0.14 mole) ofpotassium carbonate, 50.9 g (0.5 mole) of potassium bicarbonate and 510ml of dimethyl sulfoxide was stirred at room temperature for 48 hr. Themixture was diluted with 1.5 l of water, and the resulting percipitatewas collected by filtration. Recrystallization from a mixture ofmethylene chloride and ether gave off-white prisms, mp 89°-91°.

EXAMPLE 19 3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile

The preparation of3-[2-(2-fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile was conducted inthe same manner as the preparation of3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile to give off-white prisms,mp 137°-139°.

EXAMPLE 20 3-[2-(2-Chlorobenzoyl)-4-chlorophenyl]-2-propenenitrile

The preparation of3-[2-(2-chlorobenzoyl)-4-chlorophenyl]-2-propenenitrile was conducted inthe same manner as the preparation of3-(2-benzoyl-4-chlorophenyl)-2-propenenitrile to give off-white prisms,mp 140°-141°.

EXAMPLE 214-[2-(2-Fluorobenzoyl)-4-chlorophenyl]-1H-pyrazole-3-carbonitrile

A mixture of 7.0 g (24.5 mmole) of3-[4-chloro-2-(2-fluorobenzoyl)phenyl)]-2-propenenitrile, 100 ml (100mmole) of a 1M ether solution of diazomethane and 75 ml of methylenechloride was allowed to stand at room temperature for 6 hr. The excessdiazomethane was discharged by the addition of acetic acid. Theresulting solution was washed with 5% aqueous sodium bicarbonate, driedover anhydrous sodium sulfate and concentrated at reduced pressure togive an amber oil.

A mixture of 8.5 g of the amber oil, 2.0 ml (36.5 mmole) of bromine and150 ml of chloroform was stirred at room temperature for 45 min. Thevolatiles were removed at reduced pressure and the residue wasredissolved in 100 ml of chloroform. The chloroform solution was boiledon the steam bath for 30 min. The chloroform solution was washed with 5%aqueous sodium bicarbonate, dried over anhydrous sodium sulfate andconcentrated at reduced pressure to give an amber oil. Purification bycolumn chromatography (SiO₂, 100 g; eluent 5% ether in methylenechloride) gave as the major component the end product as pale yellowprisms, mp 169°-170°.

EXAMPLE 224-[2-(2-Chlorobenzoyl)-4-chlorophenyl)-1H-pyrazole-3-carbonitrile

The preparation of4-[2-(2-chlorobenzoyl)-4-chlorophenyl]-1H-pyrazolo-3-carbonitrile wasconducted in the same manner as the preparation of4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrazole-3-carbonitrile togive pale yellow prisms, mp 183°-184°.

EXAMPLE 238-Chloro-6-(2-fluorophenyl)-2H,4H-pyrazolo[3,4-d][2]benzazepine

A mixture of 2.0 g (6.1 mmole) of4-[2-(2-fluorobenzoyl)-4-chlorophenyl]-1H-pyrazole-3-carbonitrile, ca 2g. of Raney nickel, and 100 ml of acetic acid was hydrogenated on a Parrapparatus for 4 hr. The Raney nickel was removed by filtration and theacetic acid was removed at reduced pressure to give a yellow oil. Theyellow oil was poured over ice, basified with ammonium hydroxide, andextracted with methylene chloride. The methylene chloride solution waswashed with water, dried with anhydrous sodium sulfate, and concentratedat reduced pressure to give a pale yellow solid. Recrystallization froma mixture of ether and methylene chloride gave cream colored prisms, mp208°-210°.

EXAMPLE 248-Chloro-6-(2-chlorophenyl)-2H,4H-pyrazolo[3,4-d][2]benzazepine

The preparation of8-chloro-6-(2-chlorophenyl)-2H,4H-pyrazolo[3,4-d][2]benzazepine wasconducted in the same manner as the preparation of8-chloro-6-(2-fluorophenyl)-2H,4H-pyrazolo[3,4-d][2]benzazepine to givethe end product as a methylene chloride solvate as cream colored prisms,mp 142°-144° (foams).

EXAMPLE 25 3-[2-(2-Fluorobenzoyl)-4-chlorophenyl]-2-propenenitrile

A solution of 5.0 g (14 mmol) of 5-chloro-2'-fluoro-2-iodobenzophenone,2 mL (14.3 mmol) of triethylamine, 2 mL (30 mmol) of acrylonitrile and35 mg (1.5 mmol) of palladium acetate was refluxed under an atomsphereof argon for 16 hr. The mixture was diluted with 100 ml of 1Nhydrochloric acid and the resulting precipitate was collected byfiltration. The precipitate was washed with ether and air dried to givean off-white solid, mp 130°-133°.

EXAMPLE 26 (2-Chloro-5-nitrophenyl)(2-chlorophenyl)methanone

To 180 ml of concentrated sulfuric acid cooled to 0° in an ice bath wasadded 28 g (0.4 mol) of sodium nitrite in portions at such a rate thatthe temperature did not go above 10°. This mixture was warmed on a steambath until a solution formed. It was then cooled to 30° and a solutionof 110.68 g (0.4 mol) of 2-amino-5-nitro-2'-chlorobenzophenone in 300 mLof hot acetic acid was added at such a rate that the temperature did notexceed 40°. This mixture was stirred without heating for 2.5 hr, andthen poured slowly into a mixture of 800 mL of concentrated hydrochloricacid and 80 g of cuprous chloride. This mixture was heated to 80° on asteam bath for 40 min until the foaming had subsided, poured into 2 l ofwater, and allowed to stand overnight. The solid was collected, washedwith water and recrystallized from methanol to give product, mp 76°-79°.

An analytical sample prepared by recrystallization from methanol had mp78.5°-80°.

EXAMPLE 27 (2-Chlorophenyl)(2-fluoro-5-nitrophenyl)methanone

A mixture of 900 mL of dimethyl formamide, 165 mL of toluene, 65.6 g(1.13 mol) of anhydrous potassium fluoride, and 74.6 g (0.252 mol) of(2-chloro-5-nitrophenyl)(2-chlorophenyl)methanone was stirred and heatedto reflux. It was dried by distilling out 170 mL of distillate, and thenheated under reflux overnight. It was cooled in an ice bath and dilutedwith 1 l of water and 100 mL of hexane. After 1 hr the gold-coloredprecipitate was collected and dissolved in 300 mL of methylene chloride.The solution, after separation of water, was dried over sodium sulfateand concentrated in vacuo. The residue was slurried in ether (cold) toleave crude 2-nitroxanthene-9-one. The ether solution was concentratedin vacuo and the residue recrystallized from methanol to give theproduct, 60°-64°.

An analytical sample prepared by recrystallization from methanol had mp60°-64°.

EXAMPLE 28 3-(2-Chlorobenzoyl-4-nitrophenyl)-2,4-pentanedione

To a mixture of 100 mL of dimethyl sulfoxide, and 8 mL (78 mmol) ofacetylacetone cooled in a cold water bath was added 8.8 g of potassiumt-butoxide. There was an exotherm that was moderated by the addition ofice to the bath. After 0.5 hr, 11.2 g (40 mmol) of(2-chlorophenyl)(2-fluoro-5-nitrophenyl)methanone was added, and thereaction mixture was stirred 1 hr at room temperature. It was pouredinto a stirred mixture of 200 mL of ice water, 40 mL of 3N hydrochloricacid and a little ether. After 1 hr the solid was collected, washed withwater and with hexane, and recrystallized from methanol to give the endproduct.

An analytical sample prepared by recrystallization from methanol had mp138°-140°.

EXAMPLE 29[5-Nitro-2-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl]-2-chlorophenyl-methanone

A solution of 9 g (25 mmol) of3-(2-chlorobenzoyl-4-nitrophenyl)-2,4-pentanedione in 60 mL of 0.5Mhydrazine hydrochloride solution in aqueous ethanol was heated underreflux overnight and then concentrated in vacuo. The residue waspartitioned between 100 mL of methylene chloride and 50 mL of wateradjusted to pH 5 with concentrated ammonia. The organic phase wasseparated, washed with 50 mL of water, dried over sodium sulfate andconcentrated in vacuo. The residue was crystallized from ether/hexaneand recrystallized from ethyl acetate/hexane to give the end product.

An analytical sample prepared by recrystallization from ethyl acetatehad mp 160°-162°.

EXAMPLE 30(2-Chlorophenyl)[5-nitro-2-(1,3,5-trimethyl-1H-pyrazolyl)]methanone

To a mixture of 3.2 ml of methylhydrazine and 80 mL of ethanol was added7.4 mL of concentrated hydrochloric acid and 14.4 g (40 mmol) of3-(2-chlorobenzoyl-4-nitrophenyl)-2,4-pentane-dione. The mixture wasstirred and heated under reflux for 6 hr. It was concentrated in vacuoand the residue was partitioned between methylene chloride and wateradjusted to pH 6 with sodium bicarbonate. The organic phase wasseparated, dried over sodium sulfate and concentrated in vacuo. Theresidue was chromatographed over silica gel eluting with methylenechloride and 2% methanol in methylene chloride. The combined fractionsof product were crystallized from ethyl acetate to give the end product,mp 146°-150°.

An analytical sample prepared by recrystallization from ethylacetate/hexane had mp 146°-149°.

EXAMPLE 31[5-Nitro-2-[3-(chloromethyl)-5-methyl-1H-pyrazol-4-yl]phenyl]-2-chlorophenylmethanone

To a solution of 6.2 g (57.1 mmol) of t-butyl hypochlorite in 250 mL ofmethylene chloride was added 18.39 g (51.7 mmol) of the end product ofExample 32, and the reaction mixture was allowed to stand at roomtemperature for 6 hr. It was then concentrated in vacuo and the residuecrystallized from ether to give crude product.

An analytical sample prepared by recrystallization from aqueous methanolhad mp 147°-149°.

EXAMPLE 32(2-Chlorophenyl)[5-nitro-2-[3-(chloromethyl)-1,5-dimethyl-1H-pyrazol-4-yl]phenyl]methanone

To a solution of 3 g (27.6 mmol) of t-butyl hypochlorite in 100 mL ofmethylene chloride was added 9.25 g (25 mmol) of the end product ofExample 30. The reaction mixture got hot and the solvent boiled. It wasstirred overnight and then concentrated in vacuo. The residue wascollected with ether to give crude product, mp 142°-145°.

An analytical sample prepared by recrystallization from ethyl acetatehad mp 145°-147°.

EXAMPLE 336-(2-Chlorophenyl)-3-methyl-8-nitro-2H,4H-pyrazolo[3,4-d][2]benzazepine

To ca. 50 mL of liquid ammonia was added 3 g (7.7 mmol) of the endproduct of Example 34. The ammonia was allowed to evaporate for 1 hr andthen 25 ml of tetrahydrofuran was added. This mixture was heated underreflux to drive off the excess ammonia for 0.5 hr and then concentratedin vacuo. The residue was crystallized from a mixture of water and etherto give crude product.

An analytical sample prepared by recrystallization from acetonitrile wasobtained as yellow prisms, mp 237°-241° (dec.).

EXAMPLE 346-(2-Chlorophenyl)-1,2-dimethyl-8-nitro-2H,4H-pyrazolo[3,4-d][2]benzazepinez-2-butenedioic acid salt (1:1)

To a mixture of 25 mL of tetrahydrofuran, 25 mL of liquid ammonia and 1g of sodium iodide was added 5 g (12.4 mmol) of the end product ofExample 32. This reaction mixture was stirred overnight while theammonia evaporated. It was diluted with 100 mL of methylene chloride,washed with 50 mL of water, dried over sodium sulfate and concentratedin vacuo to leave a yellow tar. A solution of this tar and 1 mL ofacetic acid in 100 mL of toluene was heated under reflux under aDean-Stark water separator for 3 hr and concentrated in vacuo to ayellow oil. This was chromatographed on silica gel usingmethanol/methylene chloride (0.5%-5%) to elute. The fractions containingproduct were combined and treated with 1.35 g of maleic acid in ether toform the maleate. The solid was collected and washed with ether to givethe maleate, mp 138°-142°.

An analytical sample prepared by recrystallization from 2-propanol hadmp 135°-137°.

In a similar reaction starting with 17.1 g (42.3 mmol) of the endproduct of Example 32 there was obtained form the chromatography an oilwhich was crystallized from ether to give the end product, mp 140°-145°.

An analytical sample prepared by recrystallization from ethylacetate/hexane had mp 141°-143°.

EXAMPLE 35

    __________________________________________________________________________    TABLET FORMULATION (Wet granulation)                                          Item                                                                             Ingredients  mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                   __________________________________________________________________________    1. 8-chloro-6-(2-fluoro-                                                                      1     5     10    25                                             phenyl)-2H,4H--pyrazolo                                                       [3,4-d][2]benzaze-                                                            pine                                                                          6-(2-chlorophenyl)-3-                                                         methyl-8-nitro-2H,4H--                                                        pyrazolo[3,4-d][2]benzaze-                                                    pine                                                                       2. Lactose      202   232   261   280                                         3. Modified Starch                                                                            25    35    45    55                                          4. Pregelatinized Starch                                                                      20    25    30    35                                          5. Distilled water q.s.                                                                       --    --    --    --                                          6. Magnesium Stearate                                                                         2     3     4     5                                              Weight of tablet                                                                           250 mg                                                                              300 mg                                                                              350 mg                                                                              400 mg                                      __________________________________________________________________________

Procedure:

1. Mix Items 1-4 in a suitable mixer.

2. Granulate with sufficient distilled water to proper consistency.Mill.

3. Dry in a suitable oven.

4. Mill and mix with magnesium stearate for 3 minutes.

5. Compress on a suitable press equipped with appropriate punches.

EXAMPLE 36

    __________________________________________________________________________    TABLET FORMULATION (Direct compression)                                       Item                                                                             Ingredients  mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                   __________________________________________________________________________    1. 8-chloro-6-(2-fluoro-                                                                      1     5     10    25                                             phenyl)-2H,4H--pyrazolo                                                       [3,4-d][2]benzaze-                                                            pine                                                                          6-(2-chlorophenyl)-3-                                                         methyl-8-nitro-2H,4H--                                                        pyrazolo[3,4-d][2]benzaze-                                                    pine                                                                       2. Lactose      221   217   212   181                                         3. Avicel       45    45    45    55                                          4. Direct Compression                                                                         30    30    30    35                                             Starch                                                                     5. Magnesium stearate                                                                         3     3     3     4                                              Weight of tablet                                                                           300 mg                                                                              300 mg                                                                              300 mg                                                                              300 mg                                      __________________________________________________________________________

Procedure:

1. Mix Item 1 with an equal amount of lactose. Mix well.

2. Mix with Items 3 and 4, and the remaining amount of Item 2. Mix well.

3. Add magnesium stearate and mix for 3 minutes.

4. Compress on a suitable press equipped with appropriate punches.

EXAMPLE 37

    __________________________________________________________________________    CAPSULE FORMULATION                                                           Item                                                                             Ingredients  mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                                                           mg/tablet                                   __________________________________________________________________________    1. 8-chloro-6-(2-fluoro-                                                                      1     5     10    25                                             phenyl)-2H,4H--pyrazolo                                                       [3,4-d][2]benzaze-                                                            pine                                                                          6-(2-chlorophenyl)-3-                                                         methyl-8-nitro-2H,4H--                                                        pyrazolo[3,4-d][2]benzaze-                                                    pine                                                                       2. Lactose      203   293.5 328   372.5                                       3. Starch       30    35    40    30                                          4. Talc         15    15    20    20                                          5. Aerosol OT   1     1.5   2     2.5                                            Capsule fill weight                                                                        250 mg                                                                              350 mg                                                                              400 mg                                                                              450 mg                                      __________________________________________________________________________

Procedure:

1. Mill Items 1, 2, 3 and 5 in a suitable mixer. Mill.

2. Add talc and mix well.

3. Encapsulate on suitable equipment.

What is claimed:
 1. A compound of the formula ##STR10## wherein R₁ ishydrogen or lower alkyl; R₆ is halo and R₅ is hydrogen or halo.
 2. Acompound of the formula ##STR11## wherein R₁ is hydrogen or lower alkyl;R₆ is halo and R₅ is hydrogen or halo.
 3. A compound of the formula##STR12## wherein R₂ and R₃ are selected from the group consisting ofhydrogen, lower alkyl, C₂ to C₇ carboxylic acids, hydroxy C₂ to C₇alkyl, C₂ to C₇ carboxylic acid esters and amides and the group COR₁₁wherein R₁₁ is selected from the group consisting of alkoxy, amino ormono-lower alkyl amino; R₃₅ is hydrogen or lower alkyl and R₅ ishydrogen or halo.
 4. A compound of the formula ##STR13## wherein R₃₅ ishydrogen or lower alkyl; R₂ and R₃ are selected from the groupconsisting of hydrogen, lower alkyl, C₂ to C₇ carboxylic acids, hydroxyC₂ to C₇ alkyl, C₂ to C₇ carboxylic acid esters and amides, the groupCOR₁₁ wherein R₁₁ is selected from the group consisting of alkoxy,amino, or mono-lower alkyl amino and R₅ is hydrogen or halogen.
 5. Thecompound of claim 1 wherein R₁ is hydrogen and R₅ is halo.
 6. Thecompound of claim 2 wherein R₁ is hydrogen and R₅ is halo.
 7. Thecompound of claim 3 wherein R₃₅ is hydrogen and R₅ is halo.
 8. Thecompound of claim 7 wherein R₂ and R₃ are hydrogen or lower alkyl.